EP2652512B1 - Verwendung von ide als biomarker für kopfhauterkrankungen - Google Patents

Verwendung von ide als biomarker für kopfhauterkrankungen Download PDF

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EP2652512B1
EP2652512B1 EP11805225.7A EP11805225A EP2652512B1 EP 2652512 B1 EP2652512 B1 EP 2652512B1 EP 11805225 A EP11805225 A EP 11805225A EP 2652512 B1 EP2652512 B1 EP 2652512B1
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acid sequence
amino acid
scalp
seq
nucleic acid
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French (fr)
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EP2652512A2 (de
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Caroline Delattre
Philémon SIRVEN
Dominique Bernard
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LOreal SA
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LOreal SA
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6489—Metalloendopeptidases (3.4.24)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96486—Metalloendopeptidases (3.4.24)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/20—Dermatological disorders

Definitions

  • the present invention relates to the field of biomarkers and cosmetic and / or therapeutic targets of the skin, in particular of a dandruff condition of the scalp, and to their use as active agents.
  • the term "skin” refers to the entire epidermis of a human body, including the mucous membranes and cutaneous regions covered with hair or hair. More particularly, the skin considered in the present invention is preferably the lips, the skin of the face, the Vietnameselleté or the scalp, and more preferably still, the skin of the scalp.
  • the skin is a tissue whose cells are contiguous and integral with each other. It forms an outer coating comprising sebaceous or sweat glands, and hair follicles.
  • the skin, and especially the scalp, are epithelia with continual renewal. Renewal, or desquamation, is a coordinated and finely regulated process resulting in the elimination of surface cells, insensitively and nonvisibly.
  • abnormal or irregular desquamation of the stratum corneum cells can lead to the formation of large, thick, visible to the naked eye cells called “dander” or “dandruff” as part of the scalp, or in other situations, thinning of the stratum corneum.
  • the desquamation disorders, resulting from abnormal or irregular desquamation can lead to a fragility, even a defect of the barrier properties of the epidermis.
  • yeast Malassezia sp As examples of factors promoting the development of dander or dandruff, mention may be made of stress, the winter period, an excess of sebum, a lack of hydration, or the colonization of the skin or hair follicles by the yeast Malassezia sp .. These factors include, for commonality of cause and / or promote an inflammatory skin condition. Such inflammation enhances the appearance or even increases the presence of dander or dandruff.
  • yeasts of the Malassezia sp. Type constituting a part of the commensal flora normal to the surface of the scalp in subjects without film, see their proportion increase substantially in case of dandruff, or in case of associated seborrheic dermatitis.
  • the imbalance of the ecoflora of the scalp is a factor favoring or even reinforcing the presence of dandruff.
  • dander or dandruff can be chronic, frequent, recurrent, and socially disabling conditions because of their obvious unsightly nature.
  • skin dandruff or abnormal desquamation of the skin may result in an alteration of the epidermal barrier function, or generate sensations of itching or pruritus, leading to scraping behaviors that increase the occurrence of scales or dandruff and, in turn, scalp or skin irritation.
  • the dandruff conditions of the scalp may be of the fatty type or of the dry type.
  • the dry dandruff conditions of the scalp are more frequently manifested, and are amplified, during disorders of the hydration of the skin, and in particular during severe dryness of the epidermis of the scalp.
  • the scalp is rich in sebaceous glands, a dandruff condition can develop more easily in the presence of excessive sebum and be more easily itchy.
  • excessive secretion of sebum, or hyperseborrhoea promotes the appearance of a fatty dandruff condition of the scalp, or oily dandruff, generally associated with discomfort, sensations of discomfort, aesthetic disorders, or even cutaneous pathology.
  • the dandruff states generally respond to different local or systemic treatments.
  • the effectiveness of these treatments is only suspensive and involves rigorous monitoring by the user (frequency of use and sufficient application time).
  • a daily and long-term use of these treatments can lead to a phenomenon of habituation reducing their effectiveness, and generally associated with a phenomenon of rebound occurring at the end of the treatment. This phenomenon is manifested by a hyperseborrhea, aggravating the dandruff condition and altering the barrier function of the scalp.
  • the aggressiveness of certain antidandruff active against epidermal cells or ecoflora of the scalp can also affect the barrier functions of the latter and cause worsening of the dandruff condition.
  • the effectiveness of anti-dandruff treatments is often slow to develop and requires a rigorous application in the long term. This latency often leads to a failure to monitor treatment. As a result, many failures occur in the implementation of these treatments.
  • the object of the present invention is to satisfy these needs.
  • the present text describes the use of (i) at least one amino acid sequence encoded by a nucleic acid sequence represented by SEQ ID NO: 1, an analog or a fragment of SEQ ID NO: 1, or ii) at least one of said nucleic acid sequence, for screening for active agents or physical treatments capable of modulating the activity, expression or maturation of said amino acid sequence or of said sequence nucleic acids to prevent and / or treat abnormal desquamation of the skin, and preferably a dandruff condition of the scalp.
  • Insulin Degrading Enzyme or Insulysin, or Insulinase or IDE
  • Insulinase or IDE was found to be a sensitive and specific biomarker of a dandruff condition of the scalp.
  • the inventors have observed that the level of expression of IDE, and more particularly of peptides derived from IDE and identified by the sequences SEQ ID NO: 8 to SEQ ID NO: 14, was systematically increased in the scalps having a dandruff condition compared to non-dandruff scalps. It is the first time that a variation of the expression of the IDE is related to an abnormal desquamation of a skin. Thus, to the knowledge of the inventors, this enzyme has never been identified as a marker of abnormal desquamation, let alone of a pellicular state.
  • the term "expression" with respect to an amino acid sequence for example a protein or a peptide, or a nucleic acid sequence, for example an mRNA, its content or the variation of its content with respect to a reference.
  • the term “maturation” with respect to an amino acid sequence, for example a protein or a peptide, or a nucleic acid sequence, for example an mRNA the modifications who follow their synthesis in a cellular environment.
  • “maturation” is understood to mean post-translational modifications, such as glycosylation, farnesylation or acetylation of certain amino acids, or proteolytic steps leading to elimination of so-called “signal” or "secretory” sequences or the release of sequences having particular biological properties.
  • the term “maturation” is understood to mean, for example, the alternative splicing of a pre-mRNA.
  • the term “activity” refers to a nucleic acid sequence, for example an mRNA, its translation.
  • IDE also known as Insulysin or Insulinase
  • IGF-II insulin-growth factor II
  • somatostatin somatostatin
  • IDE IDE-amyloid deposits characteristic of Alzheimer's disease
  • Miners et al. 2009
  • She is also involved in the pathology of type II diabetes and hyperinsulinemia (Groves et al., 2003).
  • IDE could also be associated with viral sensitivity (Ali et al., 2009).
  • the present text describes the cosmetic use of an effective amount of at least one agent modulating the activity, the expression or the maturation of an amino acid sequence of the invention, or a nucleic acid sequence of the invention, as an active agent for preventing and / or treating a disorder of the barrier properties of the scalp.
  • a modulating agent is an agent inhibiting the enzymatic activity of an amino acid sequence of the invention.
  • such an inhibiting agent may be used to prevent and / or treat a dandruff condition of the scalp.
  • the term "effective amount" of a compound of the invention a sufficient and necessary amount of this compound to obtain a desired effect, and more particularly a cosmetic effect or care with regard to abnormal or irregular desquamation of the skin, and preferably a dandruff condition of the scalp.
  • the term "prevent” means reducing the risk of occurrence or slowing the occurrence of a given phenomenon, for example in the present invention, abnormal or irregular desquamation of the skin, and preferably a dandruff condition of the scalp.
  • the present text describes the use of (i) at least one amino acid sequence of the invention, or (ii) at least one nucleic acid sequence of the invention, as a biomarker of the invention. desquamation of the skin, and preferably a dandruff condition of the scalp.
  • the present invention relates to the use in vitro or ex vivo of (i) at least one amino acid sequence encoded by a nucleic acid sequence SEQ ID NO: 1, an analogue or a fragment of SEQ ID NO: 1, said analog having a sequence identity of at least 85% with the sequence SEQ ID NO: 1 and coding for an amino acid sequence having a biological activity of the same nature as the amino acid sequence encoded by the sequence SEQ ID NO: 1, said fragment comprising from 9 to 300 consecutive base pairs of the sequence SEQ ID NO: 1 and coding for an amino acid sequence having a biological activity of the same nature as the sequence of amino acid encoded by the sequence SEQ ID NO: 1, or (ii) at least one of said nucleic acid sequence, as a biomarker of a dandruff condition of the scalp.
  • biomarker means a molecule or the activity of a molecule, the presence or absence of which, the content or the degree of activity, or a variation of these parameters is characteristic. a biological, physiological or pathological process, or the impact or effect induced by the administration of an active agent or a physical treatment on such a process.
  • the present text also describes the use (i) of at least one amino acid sequence of the invention, or (ii) at least one nucleic acid sequence of the invention, to characterize the efficacy a cosmetic treatment of the skin.
  • a cosmetic treatment whose effectiveness is characterized may be a cosmetic treatment of abnormal desquamation of the skin, and preferably of a dandruff condition of the scalp.
  • the present invention relates to the use (i) of at least one amino acid sequence of the invention, or (ii) at least one nucleic acid sequence of the invention , to characterize the effectiveness of a cosmetic treatment of a dandruff condition of the scalp.
  • the present text also describes the use of (i) at least one amino acid sequence of the invention, or (ii) at least one nucleic acid sequence of the invention, to select from a set of active agents known to prevent and / or treat abnormal desquamation of the skin, and preferably a dandruff condition of the scalp, an active agent presumed to exert a maximum beneficial effect with respect to said desquamation or said film state.
  • the present invention relates to the use (i) of at least one amino acid sequence of the invention, or (ii) at least one nucleic acid sequence of the invention , to select from a set of active agents known to prevent and / or treat a dandruff condition of the scalp, an active agent presumed to exert a maximum beneficial effect with respect to said skin condition.
  • the present text further discloses the use of an effective amount (i) of at least one amino acid sequence of the invention, or (ii) at least one nucleic acid sequence of the invention or (iii) at least one modulating agent of the invention, for preparing an isolated reconstructed skin.
  • these isolated skin models can be used to reproduce a disorder of skin desquamation, and in particular a dandruff condition of the scalp.
  • the present text also describes a cosmetic process for preventing and / or treating abnormal desquamation of the skin, and preferably a dandruff condition of the scalp, in an individual in need, comprising at least one step of administering to said individual, to the at least one composition comprising as active agent at least one agent modulating the activity, the expression or the maturation of said sequences, preferably as defined below.
  • a method or a use in accordance with the invention may be carried out in vitro or ex vivo.
  • the present text describes an isolated peptide represented by an amino acid sequence selected from SEQ ID NO: 9 to SEQ ID NO: 14, an analogue or a fragment thereof.
  • the present invention relates to an isolated peptide selected from SEQ ID NO: 9 to SEQ ID NO: 14, or an analog having a sequence identity of at least 85% with said isolated peptide and having a biological activity of the same nature as said isolated peptide.
  • composition comprising a peptide represented by an amino acid sequence selected from SEQ ID NO: 8 to SEQ ID NO: 14, an analogue or a fragment thereof, or a nucleic acid sequence encoding for such a peptide.
  • the present invention relates to a composition
  • a composition comprising a peptide selected from SEQ ID NO: 9 to SEQ ID NO: 14 or an analog having a sequence identity of at least 85% with said isolated peptide and having a biological activity of the same nature as said isolated peptide or a nucleic acid sequence encoding such a peptide.
  • the present text also describes a multicellular skin model comprising at least one cell in which the expression of a protein represented by SEQ ID NO: 8, a fragment or an analogue thereof is repressed or augmented.
  • a cell model is an in vitro or ex vivo model.
  • the present invention has the advantage of proposing a new biomarker sensitive and specific to the skin, and in particular the desquamation, particularly abnormal, of the skin, and more particularly of a dandruff condition of the scalp.
  • IDE in the stratum corneum, and more particularly peptides derived specifically from this protein, advantageously makes it possible to quantitatively or qualitatively determine the expression or the activity of this protein, or peptides corresponding, by simple topical sampling.
  • the sampling method may for example be a corneodisc type or stripping technique of applying to the epidermis considered an adhesive element. By detaching this adhesive element, a fraction of the surface of the skin is removed. After protein extraction, this can then be analyzed by conventional methods, such as the enzyme immunoassay ELISA, or a Western-Blot analysis, or more particularly by the differential proteomic method by 2D electrophoresis.
  • the present invention has the advantage of being able to provide a novel biomarker suitable for screening new active agents or new physical treatments for preventing and / or treating a disorder of skin desquamation, and in particular a dandruff condition of the leather. scalp.
  • the present invention makes it possible to propose novel active agents for preventing and / or treating a disorder of the desquamation of the skin, and in particular a dandruff condition of the scalp.
  • the new active ingredients proposed by the present invention make it possible to reinforce the barrier properties of the scalp.
  • the protection and strengthening of the barrier properties of the scalp allow a reduction of the inflammatory conditions of the skin, the maintenance of a balanced barrier, its integrity and the conservation of a balanced ecoflora.
  • the scalp is then less irritated and pruriginous, less fragile and more hydrated, and the dandruff states are reduced.
  • Insulin-Degrading Enzyme or Insulysin is a protein of 1019 amino acids (SEQ ID NO: 8) comprising an initiating methionine which is eliminated, and whose gene is located on chromosome 10, locus 10q23-q25. .
  • IDE is intended to mean in this application the amino acid sequences represented by SEQ ID NO: 8, at SEQ ID NO: 14, whether or not they have undergone post-translational processing.
  • IDE is particularly intended to denote the amino acid sequence represented by SEQ ID NO: 8, and more preferably the amino acid sequence represented by a sequence derived from SEQ ID NO: 8 in which the initiating methionine has been removed.
  • an amino acid sequence suitable for the invention may be encoded by a nucleic acid sequence represented by SEQ ID NO: 1, or an analogue or a fragment of this sequence.
  • analogue of an amino acid sequence or a nucleic acid sequence according to the invention is meant any amino acid or nucleic acid sequence having a sequence identity of at least 85%, preferably at least 90%, and more preferably at least 95% with said reference sequence, and, as the case may be, having a biological activity of the same nature or coding for an amino acid sequence having a biological activity of the same nature.
  • homologous sequences identified in the Homologene database (http://www.ncbi.nlm.nih.gov/homologene).
  • analog of a nucleic acid sequence is meant in particular to designate a nucleic acid sequence resulting from the degeneracy of the nucleic acid code, and coding for an amino acid sequence according to the invention, in particular as defined above.
  • biological activity of the same nature with respect to an amino acid sequence according to the invention, is meant in particular the proteolytic properties usually attributed to IDE, such as, for example, the ability to hydrolyze insulin, bradykinin, kallidin, ⁇ -amyloid peptide or glucagon.
  • an amino acid sequence according to the invention is more particularly characterized by its ability to degrade substrates forming amyloid structures.
  • Sequence identity can be determined by visual comparison or by any computer tool commonly used in the domain, such as BLAST programs available at www.ncbi.nlm.nih.gov and used with default settings.
  • An analogue of an amino acid sequence according to the invention may be a peptidomimetic agent.
  • An analogue of an amino acid sequence of the invention may result from modifications resulting from one or more mutation (s) and / or variation (s) in the sequences of the peptides according to the invention either from the deletion or the insertion of one or more amino acids, either the substitution of one or more amino acids or alternatively splicing. Many of these changes can be combined.
  • an analogue of an amino acid sequence of the invention may comprise conservative substitutions with respect to this reference amino acid sequence.
  • hydropathic index is an index attributed to amino acids according to their hydrophobicity and their charge (Kyte et al., 1982).
  • amino acid sequence or an analogue thereof targeted by the present invention may be an amino acid sequence having undergone one or more post-translational processing (s).
  • post-translational processing is intended to encompass all the modifications that an amino acid sequence is likely to undergo at the end of its synthesis in a cell, such as, for example, a or phosphorylation (s), thiolation (s), acetylation (s), glycosylation (s), lipidation (s), such as farnesylation or palmitoylation, rearrangement Disulfide-type and / or cleavage-type structural bonding within the peptide sequence.
  • An analogue of an amino acid sequence has, moreover, substantially the same biological activity as this amino acid sequence.
  • a primary amino acid sequence may comprise sites specifically recognized by protease type enzymes, such as the trypsin, which, once recognition of these sites performed will induce cleavage of the sequence by proteolysis.
  • protease type enzymes such as the trypsin
  • the present text also describes fragments of the IDE, possibly resulting from its proteolysis.
  • fragment of an amino acid sequence any portion of the amino acid sequence according to the invention comprising at least 3 or at least 4, and more preferably at least 6 consecutive amino acids of said reference sequence, or comprising from 3 to 100 consecutive amino acids of said reference sequence, preferably from 4 to 90, preferably 6 to 80, and more preferably from 9 to 70 consecutive amino acids of said sequence, and has a biological activity of the same nature.
  • fragment of a nucleic acid sequence means a nucleic acid sequence comprising at least 9, or even at least 12, and more preferably at least 18 consecutive base pairs of said nucleic acid sequence.
  • reference sequence or comprising from 9 to 300 consecutive base pairs of said reference sequence, preferably from 12 to 270, preferably 18 to 240, and more preferably from 27 to 210 consecutive base pairs of said sequence, and coding for an amino acid sequence having a biological activity of the same nature as the amino acid sequence encoded by said sequence.
  • an amino acid sequence that is suitable for the invention may be an amino acid sequence represented by a sequence chosen from SEQ ID NO: 8 to 14, an analogue, or a fragment thereof and preferably from SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13 and SEQ ID NO: 14, an analogue, or a fragment thereof.
  • an amino acid sequence that is suitable for the invention may be natural or synthetic, where appropriate may be obtained after enzymatic or chemical lysis of the IDE or by chemical or biological synthesis or by extraction. from a biological tissue, such as the skin, naturally expressing this amino acid sequence or after transfection thereof, as well as the various post-translational forms thereof, or any acid sequence natural or synthetic amines whose sequence completely or partially comprises a aforementioned amino acid sequence, for example variants and analogs.
  • an amino acid sequence that is suitable for the invention may also be an amino acid sequence as defined above, fused with another amino acid sequence, a hydrophilic or hydrophobic targeting agent, a bioconversion precursor, a luminescent, radioactive or colorimetric labeling agent, or an antibody labeling agent.
  • examples of compounds that may be coupled to an amino acid sequence according to the invention include fluorescent proteins such as "Green Fluorescent Protein", fluorescent chemical compounds, such as rhodamine, fluorescein, or Texas Rode®, phosphorescent compounds, radioactive elements, such as 3 H , 14 C, 35 S, 121 I or 125 I, or colorimetric labeling agents such as color-sensitive substrates sensitive to galactosidase, peroxidase, chloramphenicol acetyltransferase, luciferase or alkaline phosphatase, or an antibody labeling agent, such as His-Tag.
  • fluorescent proteins such as "Green Fluorescent Protein”
  • fluorescent chemical compounds such as rhodamine, fluorescein, or Texas Rode®
  • phosphorescent compounds such as 3 H , 14 C, 35 S, 121 I or 125 I
  • radioactive elements such as 3 H , 14 C, 35 S, 121 I or 125 I
  • colorimetric labeling agents such as
  • the coupling may be carried out by chemical methods, in particular by means of reactive chemical functions or by molecular biological methods known to the art. skilled in the art.
  • the present invention also relates to nucleic acid sequences coding for an amino acid sequence of the invention, and their use in the various uses and methods of the invention.
  • the present text also describes a nucleic acid sequence, in particular of deoxyribonucleic acids, or of ribonucleic acids, represented by SEQ ID NO: 1, an analogue or a fragment thereof.
  • the present test also describes a sequence of nucleic acids, in particular deoxyribonucleic acids, or ribonucleic acids, represented by SEQ ID NO: 1 or an analogue thereof as previously defined.
  • an amino acid sequence may be encoded by a nucleic acid sequence selected from a sequence represented by SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7, an analogue or a fragment thereof.
  • a nucleic acid sequence of the invention may be represented by a sequence selected from SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7, an analogue or a fragment thereof.
  • a nucleic acid sequence of the invention may be of any possible origin, namely either animal, in particular mammalian and even more particularly human, either plant, or micro-organisms, such as for example viruses, phages, or bacteria, among others, or fungi, without prejudging the fact that they are naturally present or not in said original organism.
  • the invention also relates to the isolated and purified nucleic acid sequences coding for an amino acid sequence considered according to the invention, as well as to their analogs and fragments.
  • a nucleic acid sequence according to the invention may comprise a sense, antisense or interferential sequence corresponding to a sequence coding for a polypeptide according to the invention.
  • nucleic acid sequences in particular of ribonucleic or deoxyribonucleic acids, comprising a sense or antisense sequence, in particular "small interferent RNA” (siRNA), corresponding at least to a sequence coding for a protein or a peptide of the invention or a nucleic acid sequence of the invention, an analogue or a fragment thereof.
  • siRNA small interferent RNA
  • RNA or DNA aptamer sequences capable of modulating the activity of the enzyme.
  • the text also describes polyclonal or monoclonal antibodies obtained by conventional technologies, or preferably recombinant human antibodies selected against IDE by phage display technologies, such as those proposed by AbD Serotec, or "Nanobodies", as proposed by the company Ablynx.
  • a scalp with excessive dryness or excessive secretion of sebum may manifest a dandruff condition, which, as the case may be, may be characterized by the presence of dry or greasy dandruff or even pruritus and / or inflammation of the epidermis.
  • the dry dandruff states translate xerosis of the scalp, possibly associated with an excessively rapid renewal of its stratum corneum. Dry dandruff is usually small in size, white or gray, and spreads over the scalp and clothing that creates an unattractive visual effect. Itching associated with dryness of the scalp can lead to erythema, pruritus, or even an inflammatory condition.
  • Fatty dandruff is one of the forms of seborrheic dermatitis.
  • Affected individuals have an erythematous scalp covered by large, oily and yellow scales that accumulate to form packs. They have a pruriginous scalp, and often have burning sensations on affected areas.
  • the fatty dandruff states of the scalp are manifested, and are amplified, during an excessive secretion of sebum at the level of the epidermis of the scalp.
  • Fatty skin states in their severe forms may be forms of seborrheic dermatitis.
  • the skin barrier In the dandruff states of the scalp, the skin barrier is unbalanced, its integrity and hydration are altered and its ecoflora disturbed.
  • the skin of the scalp is irritated and itchy, fragile, less hydrated and susceptible to infections.
  • an amino acid sequence or a nucleic acid sequence of the invention or a modulating agent of the invention leads to restore hydration and ecoflora and to reduce pruritus. scalp. This reduction results in a reduction of scalp scratching phases and the resulting alteration of the barrier function. The effectiveness of the treatment is thus significantly improved and develops much more rapidly. The skin is less irritated and less pruriginous and the presence of dandruff is reduced or eliminated.
  • the invention can be implemented to prevent and / or treat a disorder of the barrier properties of the scalp.
  • the dandruff conditions of the scalp considered by the invention are distinct from the psoriasis of the scalp.
  • the present invention can be implemented with regard to the desquamation, in particular abnormal or irregular desquamation, of the skin, with a view to maintaining or restoring the homeostasis of the skin, and in particular the barrier properties of the skin. the epidermis.
  • the present invention can also be implemented to prevent and / or treat a disorder of the barrier properties of the scalp.
  • subsequent skin desquamation disorders may be either cosmetic or therapeutic. It is a matter of general knowledge, and of the usual practice, of a person skilled in the art to distinguish skin peeling disorders according to the area of which he is responsible.
  • Abnormal or irregular desquamation may result in thickening or thinning of the stratum corneum, sometimes accompanied by disorders of the barrier function of the skin.
  • skin with abnormal desquamation may be skin showing signs of dryness or xerosis, roughness, dandruff, or dander.
  • the condition of the skin may fall within the therapeutic area and present with atopic dermatitis, ichthyosis, or psoriasis.
  • a biomarker of the invention advantageously makes it possible to characterize the desquamation, in particular abnormal desquamation, of the skin, and preferably a dandruff condition of the scalp.
  • an increase or decrease in the activity, expression or maturation of a biomarker of the invention may be indicative of abnormal or irregular desquamation of the skin, and preferably a dandruff condition of the scalp.
  • an increase in the activity, expression or maturation of a biomarker of the invention may be indicative of a dandruff condition of the scalp.
  • a biomarker can be used to characterize the effectiveness of a cosmetic treatment of the skin, and particularly with regard to abnormal or irregular desquamation of the skin.
  • the cosmetic treatment whose effectiveness is characterized can be a treatment of a dandruff condition of the scalp.
  • An increase or a decrease in the activity, the expression or the maturation of the biomarker may be indicative of an effective cosmetic treatment, and in particular to exert a beneficial effect on abnormal or irregular desquamation of the skin, and in particular with regard to a dandruff condition of the scalp.
  • a decrease or increase in the activity, expression or maturation of the biomarker can be determined by comparison with a reference measurement obtained by any method known to those skilled in the art.
  • a “reference measurement” for a given parameter is a qualitative or quantitative measure of this parameter carried out under so-called “control” or “normal” conditions, for example determined in a reference sample, or determined in a sample in the absence of a treatment alleged to have an effect on the parameter.
  • a sample suitable for the invention may be an isolated skin sample taken from an individual or from a reconstructed skin model in vitro.
  • a reference measurement for an amino acid sequence or a nucleic acid sequence according to the invention may be a quantitative or qualitative value relating to the expression, the maturation or the activity of said sequences determined in a a physiologically healthy skin sample, with normal or regular desquamation, or determined in a skin sample, in particular having a desquamation disorder of the skin, before a cosmetic treatment.
  • a reference measurement is a statistical measurement, that is to say having been repeated on different samples so as to obtain an average.
  • the reference measurement can be performed in parallel or sequentially with the test measurement.
  • Such information may subsequently be used to determine the presence of normal or regular desquamation, or conversely, abnormal or irregular skin.
  • an abnormal or irregular desquamation of the skin may result in a deviation of the expression of this sequence by a factor of at least 1, 2, preferably at least 1.5, and more preferably at least twice the normal reference value.
  • the invention may also be carried out on a skin sample taken from an epidermal cellular model, or a reconstructed isolated skin in order to qualify the state.
  • a biomarker of the invention can be used to select from a set of active agents to prevent and / or treat a skin desquamation disorder, an active agent presumed to exert the maximum beneficial effect to with respect to said disorder.
  • the set of assets in which a selection of a use of the invention may be made may be the set of active agents conventionally used to treat a desquamation disorder. More particularly, a biomarker of the invention may be used for the selection of an active agent most suitable for treating an individual having a dandruff condition of the scalp. In such a case, the assets that will be considered are those usually used for the treatment of dandruff states.
  • a biomarker of the invention may advantageously be used to set up a personalized advice service for an individual presenting with a disorder of the peeling of the skin, and in particular having a dandruff condition of the scalp.
  • the counselor may make a choice to the most appropriate product so as to obtain the best correction of the biomarker compared to normal, while reducing the risk of occurrence side effects or undesirable effects that could prove to be deleterious to the good compliance of the treatment.
  • a biomarker of the invention may also be implemented in a selection and constitution process of an individual group for carrying out clinical trials dedicated to evaluating the efficacy of a product. presumed to be active with respect to abnormal desquamation of the skin, and preferably a dandruff condition of the scalp.
  • a biomarker of the invention can be used to define groups of homogeneous individuals having the same degree of deviation of the biomarker from a given value. reference.
  • the present text describes a method, in particular in vitro or ex vivo, for characterizing a state of desquamation of the skin.
  • Such a method advantageously makes it possible to characterize a disorder of skin desquamation resulting from abnormal or irregular desquamation, and more particularly a dandruff condition of the scalp.
  • such a method makes it possible to demonstrate an effect of a cosmetic treatment capable of normalizing an abnormal or irregular desquamation of the skin, and in particular a dandruff condition of the scalp.
  • such a method makes it possible to characterize the effectiveness of a cosmetic treatment, and in particular a treatment of a dandruff condition of the scalp.
  • a qualitative or quantitative measurement of expression, processing or activity of a nucleic acid sequence of the invention may be determined by any method known to those skilled in the art.
  • PCR polymerase chain reaction
  • Q-PCR quantitative
  • RT-PCR or Q-RT-PCR reverse transcriptase
  • Northern blot the "ribonuclease protection assay” method, methods with DNA chips, methods with transcriptomic chips, methods with oligonucleotide chips, hybridization methods in if you.
  • agents suitable for the detection of a nucleic acid sequence of the invention and in particular of an mRNA sequence, mention may be made of labeled nucleic acid probes which can be hybridizing to a nucleic acid sequence of the invention.
  • Such a nucleic acid probe can be easily obtained by any method known to those skilled in the art.
  • nucleic acid sequences as described in the present text can be used to produce sense and / or antisense oligonucleotide primers, which hybridize under conditions of high stringency to at least one of the sequences SEQ ID NO : 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7, an analog or fragment thereof.
  • nucleic acid sequence may also be determined, indirectly, by determining the expression of the amino acid sequence encoded by said sequence, by means of any technique known in the art, such as Western blot, ELISA, BRADFORD or LOWRY method, or as indicated below 2D electrophoresis.
  • a qualitative or quantitative measurement, expression, maturation, or activity of an amino acid sequence of the invention may be effected by any method known to those skilled in the art.
  • immunoenzymatic assay methods from more quantitative and sensitive protein solutions can in particular be used.
  • These ELISA methods combine couples of capture antibodies and specific detection of the targeted antigen.
  • Specifically developed commercial or polyclonal, monoclonal or recombinant antibodies can be used.
  • High capacity multiplexed ELISA techniques can also be implemented. It is thus possible to cite the Luminex antibody-type multiplexed approach (for example Bioplex from Bio-Rad), the single-particle or multi-chemiluminescent approach of Mesoscale Discovery (MSD), or of the antibody type on a flat surface (“ antibodies-arrays ”) (eg approach proposed by MesoScale Discovery).
  • an antibody where appropriate in a labeled form.
  • an antibody can be labeled with a directly detectable or detectable substance by reaction with another reagent.
  • antibodies is generally meant monoclonal or polyclonal antibodies, as well as immunoglobulin fragments capable of binding an antigen and which may be produced by any genetic engineering technique known to those skilled in the art. by enzymatic or chemical cleavage of intact antibody.
  • An antibody that can be used as a tool for evaluating a state of an epidermis can be obtained by any method known to those skilled in the art, as described in US Pat. "Antibodies: A Laboratory Manual,” Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (1990). ).
  • an amino acid sequence of the invention may be advantageous to detect the expression of an amino acid sequence of the invention by means of a differential proteomic method by 2D electrophoresis approach or by an iTRAQ isobaric labeling approach, by a label free Spectral Counting approach or SILAC type if it involves cell cultures.
  • activity with respect to an amino acid sequence of the invention is meant a proteolytic activity as indicated above, or an activity of reduction, prevention or treatment of a disorder of the desquamation of a skin, for example as defined above, and in particular a dandruff condition of the scalp.
  • Such activity can be determined by any method known to those skilled in the art, such as, for example, by evaluating a proteolytic activity on a usual substrate of IDE such as insulin, glucagon or ⁇ protein. -amyloid.
  • the determination of a state of the skin or the characterization of the effectiveness of a cosmetic treatment of the skin can be carried out by measuring the variation of the expression of an amino acid sequence of the skin.
  • invention and preferably represented by a sequence selected from SEQ ID NO: 8 to SEQ ID NO: 14, an analogue or a fragment thereof.
  • the methods of the invention are particularly advantageous in that their implementation does not require the use of an invasive technique.
  • a sample epidermis can thus be obtained by so-called "stripping" techniques and directly analyzed by a conventional analysis technique known to those skilled in the art.
  • strippings are tacky surfaces applied to the surface of the epidermis such as Blenderm® 3M, D'squam (commercial adhesive CuDERM), cyanoacrylate glue, the method of "stripping” varnish or corneodisques. Thanks to these "strippings", adherent corneocytes and the contents of their intercellular spaces can be removed and subsequently subjected to an extraction allowing access to the protein content.
  • Sampling of a sample suitable for a process of the invention may also be carried out more directly by "washing" the skin surface, for example by means of turbine-type propellers such as spiral cells. as described in the patent FR 2,667,778 associated with a fluidic circuit, or simply by adding / removing a drop of buffer on the surface of the skin.
  • one of the markers of the invention can be used for purposes of preclinical selection, more effective and more rigorous, of individuals, with a view to evaluating the effectiveness of treatment or cosmetic active for the care of the skin, and especially the scalp.
  • a biomarker of the invention may advantageously be used as indicated above to evaluate the efficacy of an active agent, in vitro, ex vivo or in vivo.
  • a biomarker of the invention can be used to establish a personalized advice of a cosmetic treatment for an individual according to its expression profile of cutaneous biomarkers.
  • the present text describes the use of a biomarker of the invention, for screening or in a screening method, in particular in vitro or ex vivo, of active agents or physical treatments for the treatment. skin.
  • the active agents or the screened physical treatments can in particular be used to prevent and / or treat abnormal or irregular desquamation of the skin, and preferably to prevent and / or treat a dandruff condition of the scalp.
  • a use or a screening method may comprise comparing a measurement of the activity, expression or processing of an amino acid sequence or nucleic acid sequence according to the invention. to a reference measure.
  • a reference measurement may be as previously defined.
  • a reference measurement may be a quantitative or qualitative value relative to the expression, the maturation or the activity of said sequences determined in a sample in the absence of active agent or physical treatment tested.
  • a reference measurement can be obtained by repeating the steps of a method of the invention, and in particular steps a), b) and c) of a method of the invention as defined above, in the absence of active agents, or physical treatments to be tested.
  • the quantitative or qualitative determination of the expression, the maturation or the activity of an amino acid sequence or of a nucleic acid sequence of the invention may be carried out by any method known to man of art, and especially as described above.
  • the screening of an active agent or a physical treatment capable of modulating the activity of an amino acid sequence of the invention can be done by measuring the activity or the expressing a target molecule belonging to the signaling or metabolism pathways in which may be involved said of an amino acid sequence, such as for example a reporter gene system.
  • a method of the invention can be implemented in a cell-free system, i.e. in a system not comprising cells but reproducing cellular functions, or in an isolated cell sample.
  • a method according to the invention can be carried out on an isolated cell sample, an acellular sample, an isolated amino acid sequence or an isolated nucleic acid sequence of the invention.
  • samples or sequences can be obtained by cutaneous biopsy, from cells in culture, in particular from an epidermal model, or from a non-invasive skin surface sample, in particular by adhesive (" Stratum corneum " stratum corneum) or by simple washing, as described above, or, in terms of sequences, by synthesis.
  • a cellular sample that is suitable for the invention, there may be mentioned a sample of keratinocytes or any other cell type of the skin expressing an amino acid sequence of the invention.
  • the screening of an active agent or a physical treatment can be carried out by measuring the variation of the expression or the activity, in the presence and absence of the active agent or the physical treatment screened.
  • an amino acid sequence of the invention and preferably represented by a sequence selected from SEQ ID NO: 8 to SEQ ID NO: 14, an analogue or a fragment thereof, and preferably selected from SEQ ID NO: 9 to SEQ ID NO: 14, an analogue or fragment thereof.
  • the term “modulating agent” or “active agent or physical treatment capable of modulating the expression, the maturation or the activity of an amino acid sequence or a sequence of nucleic acids according to the invention any compound or physical phenomenon capable of acting, directly or indirectly, on at least one amino acid sequence or a nucleic acid sequence in accordance with the invention, or on a d an intra- or extracellular signaling pathway, or a metabolic pathway, or transcriptional and / or translational regulation involving said amino acid sequence or said nucleic acid sequence.
  • the modulating agents or the physical treatments that are preferred according to the present text may be compounds or physical treatments acting directly on at least one amino acid sequence of the invention or at least one nucleic acid sequence of the invention in view of modulate their expression, or their maturation, or their activity.
  • the active agents or the physical treatments resulting from a screening described in the present text can be advantageously used for cosmetic purposes, in particular with regard to skin desquamation disorders, in particular disorders of the barrier properties of the skin, and in particular particular disorders of the barrier properties of the scalp.
  • a modulating agent of the invention is an agent which inhibits the activity, the expression or the maturation of an amino acid sequence of the invention. More preferably, a modulating agent is an agent inhibiting the enzymatic activity of an amino acid sequence of the invention.
  • hydroxamate peptides that are suitable for the invention are more particularly described in WO 2008/156701 .
  • hydroxamate peptide can be chosen from: or or or
  • inhibitors of IDE of nucleoside phosphate type compounds or peptide fragments of IDE, as well as interfering RNAs, DNA or RNA aptamers or antibodies blocking the active site or the exosite of the enzyme.
  • a modulating agent in particular an agent inhibiting the activity, expression or maturation of an amino acid sequence of the invention may advantageously be used to prevent and / or treat a dandruff condition of the scalp.
  • the present text describes the use of a modulating agent inhibiting the enzymatic activity of an amino acid sequence of the invention for preventing and / or treating a dandruff condition of the scalp.
  • the present text also describes modulating agents of the invention chosen from activating agents for the activity, the expression or the maturation of an amino acid sequence of the invention and in particular activators. of the enzymatic activity of an amino acid sequence of the invention.
  • a modulator agent activating the enzymatic activity may be chosen from suramin, somatostatin, bradykinin, ⁇ -endorphin, dynorphine, ATP, iPPP, ADP, AMP, fatty acids, especially such as docosahexaenoic acid, and the compounds of the following formulas: or
  • activating agents for the enzymatic activity of IDE mention may also be made of nucleoside phosphates, peptide fragments of IDE, or activating antibodies of the enzyme.
  • RNA or DNA As a modulating agent that can be screened according to a use or a process described in the present text, mention may also be made of the antibodies, in particular derived from recombinant antibody libraries, for example from the company ANTIBODIES BY DESIGN, and suitable blocking the active site or exosite of the enzyme, or activating the enzyme, for example by allosteric effect, or interfering RNAs, such as siRNAs, miRNAs or shRNAs, or RNA or DNA.
  • compositions in particular cosmetic compositions, comprising in a physiologically or cosmetically acceptable medium an effective amount of at least one amino acid sequence of the invention, or at least one nucleic acid sequence. of the invention, or at least one active agent capable of modulating the activity, the expression or the maturation of said amino acid sequence or of said nucleic acid sequence.
  • the text describes a cosmetic composition
  • a cosmetic composition comprising a peptide represented by an amino acid sequence selected from SEQ ID NO: 9 to SEQ ID NO: 14, an analogue or a fragment thereof or a nucleic acid sequence coding for such a peptide.
  • physiologically acceptable medium is intended to mean a medium that is suitable for the administration of a composition topically to the skin, the scalp, or the lips, or orally or by the route. parenteral, such as the intradermal or subcutaneous route.
  • a composition of the invention may contain adjuvants customary in the field in question, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, perfumes, fillers, filters, absorbers odor and coloring matter.
  • adjuvants customary in the field in question such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, perfumes, fillers, filters, absorbers odor and coloring matter.
  • compositions according to the invention are those conventionally used in the fields under consideration.
  • the amount of amino acid sequence, or nucleic acid sequence of the invention, or active agent contained in a composition of the invention, also called “effective amount” is, of course, depending on the nature of the asset and the effect sought and may therefore vary to a large extent.
  • a composition may contain an amino acid sequence, or a nucleic acid sequence, or an active agent according to the invention in an amount representing from 0.00001% to 50% of the total weight of the composition, in particular in an amount representing from 0.001% to 10% of the total weight of the composition, and more particularly in an amount representing from 0.1% to 1% of the total weight of the composition.
  • a cosmetic composition of the invention may comprise, in addition, at least one additional active cosmetic and / or therapeutic agent.
  • cosmetic oils such as silicone oils, vegetable oils of the triglyceride type, and hydrocarbon oils such as PARLEAM oil. and esters of fatty acids and fatty alcohol.
  • enzymes having an activity on the skin and / or its annexes such as proteases, lipases, glucosidases, amidases, cerebrosidases and / or melanases, and mixtures thereof.
  • active agents include: analgesic active agents, anti-yeast active agents, antibacterial active agents, antiparasitic active agents, antifungal active agents, antiviral active agents, anti-inflammatory active agents steroidal agents, anesthetic active agents, antipruritic active ingredients, keratolytic active agents, anti-free radical active agents, anti-seborrhoeic active ingredients, anti-dandruff active ingredients, anti-acne active agents, active agents to prevent skin aging and / or to improve its condition, anti-dermatitis active ingredients, anti-irritant active ingredients, immunomodulatory active ingredients, active ingredients for the treatment of dry skin, antiperspirant active ingredients, anti-psoriatic active ingredients, UV protective active ingredients, antihistamine active ingredients, healing active ingredients, self-tanning active ingredients, antioxidants such as green tea or active fractions thereof, glycerin, laponite, caffeine, aromatic essential oils, dyes, depigmenting agents, lipo-regulators
  • Tween 20 or other mild detergents, chelating agents, probiotics, Zn-pyrithione or other antifungals, elagic acid, prodesquamants and / or peels, anti-pruritic compounds, polyphenols and their derivatives, reducing sugars and sugars, anti-inflammatories, anti-sweat, or anti-sebaceous, etc.
  • the present text describes the cosmetic use of an effective amount of at least one agent modulating the activity, expression or maturation of said amino acid sequence or said nucleic acid sequence, and in particular a modulating agent as defined above, as an active agent for preventing and / or treating abnormal or irregular desquamation of the skin, in particular a disorder of the barrier properties of the scalp, and preferably a dandruff condition of the scalp .
  • such a use can implement a modulating agent inhibiting the activity, the expression or the maturation of an amino acid sequence of the invention, and preferably an inhibitor of the enzymatic activity of an amino acid sequence of the invention.
  • a modulating agent inhibiting the activity, the expression or the maturation of an amino acid sequence of the invention, and preferably an inhibitor of the enzymatic activity of an amino acid sequence of the invention.
  • Such an agent may in particular be chosen from the inhibiting agents defined above.
  • such a use can implement a modulating agent activating the enzymatic activity of an amino acid sequence of the invention advantageously chosen from the activating agents defined above.
  • the present text describes a cosmetic process, or non-therapeutic, for preventing and / or treating abnormal or irregular desquamation of the skin, and in particular a dandruff condition of the scalp, in an individual in need thereof.
  • Such a method may comprise at least one step of administering to said individual, at least one composition comprising as active agent at least one agent modulating the activity, the expression or the maturation of said sequences of the invention , especially as defined above.
  • a modulator agent considered is an agent inhibiting the enzymatic activity of an amino acid sequence of the invention, in particular as defined above.
  • Such a method or such use makes it possible to prevent and / or treat a desquamation disorder of the skin, especially as defined above and, preferably, a dandruff condition of the scalp.
  • a method of using the invention can reduce the number and size of dander or dandruff.
  • a scalp can see its improved aesthetic appearance and its barrier function properties restored following the implementation of a use or a method described above.
  • such a method or such a use makes it possible to reinforce the barrier properties of the skin, and in particular of the scalp.
  • such a method may comprise the topical application to at least a portion of the skin of an individual in need, in particular on the scalp, of at least one layer of a topical composition of the invention.
  • a topical cosmetic process as described may advantageously comprise the application of a composition of the invention, in combination simultaneously, sequentially or separated in time with an additional cosmetic or dermatological composition distinct from the composition of the composition. invention and intended for the care and / or makeup of the skin, and preferably for the care of the scalp.
  • such a cosmetic process can be carried out orally, in particular by administering at least one food or dietary composition for cosmetic purposes.
  • such a cosmetic process can be carried out parenterally.
  • the parenteral use of such a cosmetic process is performed to the exclusion of any surgical procedure and is intended only to exert a surface treatment of the skin for aesthetic purposes.
  • parenteral cosmetic process is carried out by any injection technique or device that is suitable for intra-epidermal and / or intradermal and / or subcutaneous injection.
  • Such administration may be effected, for example, by mesotherapy.
  • a cosmetic process parenterally is therefore translated only by a superficial break in the skin and therefore goes out of any medical or therapeutic setting.
  • systemic patch administration may be preferred.
  • a cosmetic process as described can be carried out daily, for example because of a single administration per day, or a divided administration in two or three times a day, for example once in the morning and once. the evening.
  • a cosmetic process according to the invention may be carried out over a period of time varying from one week to several weeks, or even several months, this period being able to be repeated after periods of non-treatment for several months or even several years. .
  • a cosmetic process described above can be provided for administering a composition of the invention, for example, at a rate of 1, 2 or 3 times a day, or more, and generally over a period of time. extended by at least 4 weeks, or even 4 to 15 weeks, with one or more periods of interruption if necessary.
  • the present text describes the use of an effective amount of at least one amino acid sequence of the invention, or at least one nucleic acid sequence of the invention, or at least one modulating agent for preparing isolated reconstructed skin.
  • a use of the invention can make it possible to obtain an isolated reconstructed skin model reproducing desquamation of the skin.
  • an activating modulating agent as defined above, can be considered for the preparation of a skin model reproducing desquamation, preferably reproducing in a pellicle state.
  • the present text describes a method of preparing an isolated pluristratified epithelial cell model, and preferably an isolated reconstructed skin comprising at least the step of contacting at least one effective amount of at least one amino acid sequence, or at least one nucleic acid sequence according to the invention, or at least one modulating agent with cells capable of generating isolated reconstructed skin, and in particular keratinocytes.
  • a reconstructed skin model can include different cell types, such as keratinocytes, fibroblasts, Langerhans cells and melanocytes.
  • the fibroblast type cells may be irradiated or not.
  • a reconstructed skin model can be used as a model of a scalp.
  • An isolated reconstructed scalp model may advantageously be used for the purpose of screening new active agents suitable for the care of the scalp, and more particularly new anti-dandruff active agents.
  • the present text also describes a process for preparing a pluristratified epithelial cell model, preferably a reconstructed skin model, comprising at least one step of culturing cells of at least one cell type of said cell. model, said cells having been genetically modified to suppress or increase the expression of an amino acid sequence or a nucleic acid sequence of the invention.
  • knockout cells cells genetically modified to suppress the expression of an amino acid sequence or of a nucleic acid sequence of the invention, called “knockout” cells, can be carried out by any known method of the skilled person.
  • such cells can be obtained by transfection and homologous recombination of a nucleic acid fragment that is inserted into or takes the place of the gene expressing the amino acid sequence whose expression is to be deleted. .
  • Obtaining genetically modified cells to increase the expression of an amino acid sequence or a nucleic acid sequence of the invention can be achieved by any method known to those skilled in the art.
  • such cells can be obtained by plasmid transfection comprising a gene coding for an amino acid sequence of the invention under the control of a promoter.
  • the promoter used may allow expression of the gene inducibly or constitutively, or in a tissue-specific manner.
  • transfection vectors allowing the introduction of the gene to be expressed in the chromosomes of the cells to be transfected.
  • the study is carried out on 6 non-dermal volunteers (adherent film grade from 0 to 0.25) and 6 pellicular volunteers (adhesive film grade from 3.25 to 4).
  • the volunteers are short-haired men from 36 to 39 years old.
  • the gradation of the dandruff states of the volunteers is carried out by an expert according to the following standard classification or provides a score scale of adherent films between 0 and 5.
  • Samples are taken by corneodisc (reference GODS100, CuDerm) on 1 zone of 2cm. Four saturation corneodisks are made for each sample. The soluble proteins are extracted in a native buffer (TBS, 1M NaCl, 1% triton X100).
  • the proteins are precipitated by the addition of acetone.
  • the protein pellet is dissolved in extraction buffer III (BioRad, Ref: 163-2104) supplemented with 40 mM of DTT.
  • two-dimensional electrophoresis is carried out according to a first dimension by IEF separation pH 3-11 on 11 cm strip (GE-Healthcare) and in a second dimension on a Critérien gradient gel 10.5- 14% Bio-Rad) according to the recommendations of the suppliers.
  • a first step the images are aligned together and the intensities normalized.
  • a second step after defining groups, a statistical analysis is performed by Progenesis Samespots software (NonLinear Dynamics). A selection of spots is made according to the "p value” (less than 0.05), the "fold” (greater than 2, intensity ratio between the most intense spot of a group and the spot the least intense from another group) and the "q value” (greater than 0.8).
  • the selected spots are then cut, the proteins are digested with trypsin and analyzed by LC-MS / MS.
  • the protein library UniRef100.15.3.9606.homo-sapiens was queried to identify the proteins.
  • the IDE is identified among the selected spots in favor of overexpression in the film group according to the criteria defined above.
  • IDE as a biomarker of the skin, in particular desquamation of the skin, and more particularly of a dandruff condition of the scalp.
  • the IDE can thus be advantageously used for the screening of active ingredients for treating a dandruff condition of the scalp or for characterizing the effectiveness of a cosmetic treatment of the skin.
  • Example 2 The concentration of the samples previously described in Example 1 is aligned, and 2 ⁇ g are deposited in the wells of a 10-20% Criterion gel (BioRad). The proteins are thus separated by SDS-PAGE electrophoresis. After semi-dry transfer on a PVDF membrane according to a standard protocol, the proteins are incubated with a primary antibody directed against the protein of interest overnight at 4 ° C. A second incubation is then performed with a secondary antibody (coupled to a peroxidase) directed against the first antibody.
  • a primary antibody directed against the protein of interest overnight at 4 ° C.
  • a second incubation is then performed with a secondary antibody (coupled to a peroxidase) directed against the first antibody.
  • An electro-chemiluminescence kit is used to reveal the targeted proteins.
  • the image is acquired with FluorSmax (Biorad) and the quantified bands using Quantity-One software (Biorad).
  • Quantity-One software Biorad.
  • a commercial anti-IDE antibody was used at the 1: 5000 dilution (reference AB28560, AbCam)
  • the Figure 3 highlights the image of the Western Blot obtained.
  • the average intensity of the detected bands is represented by the histogram in Figure 4 .

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Claims (9)

  1. Verwendung, in vitro oder ex vivo (i) von mindestens einer Aminosäurensequenz, die von einer Nukleinsäurensequenz SEQ ID NO: 1, einem Analog oder einem Fragment von SEQ ID NO: 1 kodiert wird, wobei das Analog eine Sequenzidentiät von mindestens 85 % mit der Sequenz SEQ ID NO: 1 aufweist und eine Aminosäurensequenz mit einer biologischen Aktivität der gleichen Art wie die von der Sequenz SEQ ID NO: 1 kodierte Aminosäurensequenz kodiert, wobei das Fragment von 9 bis 300 aufeinanderfolgende Basenpaare der Sequenz SEQ ID NO: 1 umfasst und eine Aminosäurensequenz mit einer biologischen Aktivität der gleichen Art wie die von der Sequenz SEQ ID NO: 1 kodierte Aminosäurensequenz kodiert, oder (ii) von mindestens der Nukleinsäurensequenz, als Biomarker einer Kopfhauterkrankung.
  2. Verwendung nach dem vorangehenden Anspruch, wobei die Nukleinsäurensequenz ausgewählt ist aus SEQ ID NO: 2 bis SEQ ID NO: 7, oder einem Analog davon, wobei das Analog eine Sequenzidentiät von mindestens 85 % mit der Nukleinsäurensequenz aufweist und eine Aminosäurensequenz mit einer biologischen Aktivität der gleichen Art wie die von der Nukleinsäurensequenz kodierte Aminosäurensequenz kodiert.
  3. Verwendung nach Anspruch 1 oder 2, wobei die Aminosäurensequenz ausgewählt ist aus SEQ ID NO: 8 bis SEQ ID NO: 14, oder einem Analog davon, wobei das Analog eine Sequenzidentiät von mindestens 85 % mit der Aminosäurensequenz aufweist und mit einer biologischen Aktivität der gleichen Art wie die Aminosäurensequenz.
  4. Verwendung, in vitro oder ex vivo, (i) von mindestens einer Aminosäurensequenz nach einem der Ansprüche 1 bis 3, oder (ii) von mindestens einer Nukleinsäurensequenz nach den Ansprüchen 1 oder 2, zur Charakterisierung der Wirksamkeit einer kosmetischen Behandlung einer Kopfhauterkrankung.
  5. Verwendung, in vitro oder ex vivo, (i) von mindestens einer Aminosäurensequenz nach den Ansprüchen 1 bis 3, oder (ii) von mindestens einer Nukleinsäurensequenz nach den Ansprüchen 1 oder 2, zur Selektion aus einer Gesamtheit von Wirkstoffen, die bekanntermaßen eine Kopfhauterkrankung verhindern und/oder behandeln, eines Wirkstoffs, der geschätzt eine besonders gesundheitsfördernde Wirkung hinsichtlich der Kopfhauterkrankung ausübt.
  6. In-vitro- oder Ex-vivo-Verfahren zur Charakterisierung einer Kopfhauterkrankung, umfassend mindestens die folgenden Schritte:
    a) Durchführens in einer isolierte Probe einer Kopfhaut einer Messung der Expression, der Maturation oder der Aktivität einer Aminosäurensequenz nach den Ansprüchen 1 bis 3, und
    b) Vergleichen der in Schritt a) durchgeführten Messung mit einer Referenzmessung;
    wobei eine Steigerung der Aktivität, der Expression oder der Maturation der Aminosäurensequenz ein Hinweis ist auf eine Kopfhauterkrankung.
  7. Kosmetisches In-vitro- oder Ex-vivo-Verfahren zur Charakterisierung der Wirksamkeit einer kosmetischen Behandlung einer Kopfhauterkrankung bei einem Individuum, das Bedarf daran hat, umfassend mindestens die folgenden Schritte:
    a) Durchführen, vor der Durchführung der kosmetischen Behandlung, in einer ersten Probe der von einem Individuum entnommenen isolierten Kopfhaut, mindestens einer ersten Messung der Expression, der Maturation oder der Aktivität von mindestens einer Aminosäurensequenz nach den Ansprüchen1 bis 3, oder von mindestens einer Nukleinsäurensequenz nach den Ansprüchen 1 oder 2,
    b) Durchführen, nach der Durchführung der kosmetischen Behandlung, in einer zweiten Probe der von einem Individuum entnommenen isolierten Kopfhaut, mindestens einer zweiten qualitativen oder quantitativen Messung, der Expression, der Maturation oder der Aktivität der Aminosäurensequenz oder der Nukleinsäurensequenz, und
    c) Vergleichen der ersten und der zweiten Messungen, insbesondere um eine Information bezüglich einer Wirkung von mindestens der Durchführung der kosmetischen Behandlung abzuleiten.
  8. Isoliertes Peptid, ausgewählt aus SEQ ID NO: 9 bis SEQ ID NO: 14, oder einem Analog mit einer Sequenzidentiät von mindestens 85 % mit dem isolierten Peptide und mit einer biologischen Aktivität der gleichen Art wie das isolierte Peptid.
  9. Zusammensetzung, umfassend ein Peptid wie im vorangehenden Anspruch definiert, oder eine Nukleinsäurensequenz, die ein solches Peptid kodiert.
EP11805225.7A 2010-12-13 2011-12-12 Verwendung von ide als biomarker für kopfhauterkrankungen Active EP2652512B1 (de)

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FR1060429A FR2968560A1 (fr) 2010-12-13 2010-12-13 Utilisation de l'ide comme biomarqueur d'un etat du cuir chevelu
US201061457083P 2010-12-23 2010-12-23
PCT/IB2011/055600 WO2012080929A2 (fr) 2010-12-13 2011-12-12 Utilisation de l'ide comme biomarqueur d'un etat du cuir chevelu

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FR3070494B1 (fr) * 2017-08-23 2022-07-01 Oreal Methode de diagnostic d'une peau presentant des signes de vieillissement
JP6703218B1 (ja) * 2019-03-28 2020-06-03 株式会社ファンケル 皮膚の状態を評価する方法
CN112020642A (zh) * 2019-03-28 2020-12-01 株式会社芳珂 评价皮肤状态的方法
US11741523B2 (en) 2019-07-31 2023-08-29 L'oreal Personalized skincare recommendations based on biomarker analysis
US11501356B2 (en) 2019-07-31 2022-11-15 L'oreal Systems and methods for generating personalized skincare formulations based on biomarker analysis
JP7467594B2 (ja) * 2019-07-31 2024-04-15 ロレアル パーソナライズスキンケアのためにバイオマーカー解析を使用するためのシステムおよび方法

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KR101967489B1 (ko) 2019-04-09
BR112013014575B1 (pt) 2022-05-31
WO2012080929A2 (fr) 2012-06-21
CN103384830B (zh) 2017-05-24
US20130337085A1 (en) 2013-12-19
CN103384830A (zh) 2013-11-06
BR112013014575A2 (pt) 2018-03-20
FR2968560A1 (fr) 2012-06-15
ES2671226T3 (es) 2018-06-05
US10351838B2 (en) 2019-07-16
KR20130135887A (ko) 2013-12-11

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